Mutations in cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED/EDM1) both of which are associated with chronic joint abnormalities. The focus of this research is to determine whether the cellular pathology caused by the dominant negative effects of mutations in cartilage oligomeric matrix protein (COMP) can be reversed. In our previous work, we have demonstrated that mutations in COMP impede calcium-binding which is required for protein folding. Improperly folded mutant COMP is retained in enlarged rERcisternae along with type IX collagen, matrillin-3 and numerous chaperone proteins. This retention has the downstream effect of causing an extracellular matrix that is deficient in these proteins, a grossly disorganized matrix and eventual chondrocyte death. In contrast COMP null mice are normal suggesting that COMP is not necessary for cartilage and bone development and homeostasis. We hypothesize that removal of mutant COMP will reverse and established PSACH cellular phenotype and restore chondrocyte function and normal matrix formation. To test this hypothesis, we will now define the temporal pathway of the pathology and its resolution by using an inducible promoter system. We have successfully over-expressed mutant COMP in a 3-D culture system to recapitulate the disease pathology in normal human chondrocytes. The tetracycline (TET) inducible promoter and DMA expressing the TET-activated transcription factor (rtTA) will be used to both induce the cellular phenotype and to repress the production of mutant COMP. These experiments will be conducted in human primary growth plate chondrocytes and in transgenic mice. These studies will allow us to determine the timing of phenotype development and whether the phenotype is reversible, which is an important step towards toward developing a treatment intervention for these debilitating orthopedic dwarfing conditions.